Process for producing crystalline atorvastatin calcium

Abstract

A factory scale process for producing crystalline atorvastatin calcium includes the step of drying the isolated product in a vacuum pan dryer. The vacuum pan dryer has an agitator which is continuously rotated at a speed of approximately 1 rpm. High quality material is routinely and consistently produced with reduced cycle time.

What is claimed is:  
     
       1. A factory scale process for producing crystalline atorvastatin trihydrate hemi calcium salt comprising the steps of: 
       (a) reacting a mixture of atorvastatin lactone, methanol, and methyl tert-butyl ether with sodium hydroxide to form the ring-opened sodium salt;  
       (b) forming a product rich aqueous layer and an organic layer comprising methyl tert-butyl ether containing impurities;  
       (c) removing the organic layer comprising methyl tert-butyl ether containing impurities;  
       (d) extracting the product rich aqueous layer with methyl tert-butyl ether;  
       (e) adding an extra charge of methyl tert-butyl ether to a vessel containing the product rich aqueous layer in an amount of at least 1% w/v of the contents of the vessel;  
       (f) sealing the reaction vessel;  
       (g) heating the contents of the sealed reaction vessel to 47° C. to 57° C. in the presence of the extra charge of methyl tert-butyl ether which saturates the crystallization matrix on heating;  
       (h) adding calcium acetate hemihydrate to the sealed reaction vessel and shortly after commencement of the calcium acetate addition the transfer is stopped and the reaction mixture is seeded with crystalline atorvastatin calcium to form atorvastatin trihydrate hemi calcium salt;  
       (i) providing a vacuum pan dryer having an agitator; and  
       (j) drying the isolated product in a vacuum pan dryer whilst continuously rotating the agitator at a speed of from 0.5 rpm to 2 rpm.  
     
     
       2. The process as claimed in  claim 1  comprising continuously rotating the agitator at a speed of approximately 1 rpm. 
     
     
       3. The process as claimed in  claim 1  comprising maintaining vacuum in the pan dryer at a pressure of from −0.80 to −0.99 bar. 
     
     
       4. The process as claimed in  claim 2  comprising maintaining vacuum in the pan dryer at a pressure of from −0.80 to −0.99 bar. 
     
     
       5. The process as claimed in  claim 1  comprising drying the isolated product over a period of from 1 to 4 days. 
     
     
       6. The process as claimed in  claim 2  comprising drying the isolated product over a period of from 1 to 4 days. 
     
     
       7. The process as claimed in  claim 1  comprising drying the isolated product over a period of from 1 to 2 days. 
     
     
       8. The process as claimed in  claim 2  comprising drying the isolated product over a period of from 1 to 2 days.